Discoidin Domain Receptor 1 (also referred to as DDR1, EDDR1, NEP, NTRK1 or CAK; hereinafter referred to as DDR1) is a receptor tyrosine kinase (RTK) having a molecular weight of 105 kDa that was cloned from human placental tissue as a homologous protein of RTK (Non-Patent Document 1). It is known to induce signal transduction to downstream molecules through its autophosphorylation that occurs as a result of binding with collagen, which is the ligand (Non-Patent Document 2). DDR1 is a single-pass transmembrane receptor, and its extracellular domain is composed of a discoidin (DS) domain and stalk domain from the N-terminal; the former is required for binding to collagen, while the latter is required for dimerization of DDR1, and both have been reported to be required for autophosphorylation of DDR1 by collagen (Non-Patent Documents 3 and 4).
Suggested molecular functions of DDR1 are contribution to cellular morphological changes, adhesion, cell migration, infiltration, proliferation, inhibition of apoptosis, and the like. Experimental findings serving as the basis for these presumed functions are based on phenotype analyses of DDR1-overexpressing strains or DDR1 expression-suppressed strains, and phenomena occurring in cells induced by collagen treatment. Experimental findings including adhesion and increased infiltration in macrophages (Non-Patent Document 5), increased infiltration ability and suppression of apoptosis in human prostate cancer cells (Non-Patent Document 6), suppression of apoptosis and increased proliferation in human colorectal cancer cells (Non-Patent Document 7), and increased cell migration ability and increased infiltration ability in human lung cancer cells (Non-Patent Document 8) have been reported thus far, strongly suggesting involvement of the molecular functions of DDR1 in cancer proliferation and metastasis. In addition, high expression and activity levels of DDR1 in cancer tissue have been reported in multiple types of cancer as indicated in the following cases: glioma (Non-Patent Document 9), breast cancer (Non-Patent Document 10), endometrial cancer (Non-Patent Document 11), ovarian cancer (Non-Patent Document 12), lung cancer (Non-Patent Document 13) and bile duct cancer (Non-Patent Document 14). In addition, the correlation between expression of DDR1 and the prognosis and metastasis of cancer has been reported in glioma (Non-Patent Document 15) and lung cancer (Non-Patent Document 8). On the other hand, the existence of a function of DDR1 that is not mediated by collagen binding activity or kinase activity has also been suggested in recent years (Non-Patent Document 16), thus indicating that there are still aspects of the mechanism of action of DDR1 that remain unknown.
With respect to using DDR1 as a target of cancer therapy, an approach has already been disclosed based on the potential for screening cancer therapeutic agents, by using as indicators, DDR1-mediated phenomena (such as phosphorylation) and measuring whether or not they are inhibited, based on experimental results which indicate that DDR1 is highly expressed in cancer cells of breast cancer or the like (Patent Document 1). In addition, polyclonal antibodies to DDR1 have been prepared, which have been reported to neutralize binding between DDR1 and collagen as well as suppress the cell protective action of collagen in cancer cells (Patent Document 2). Moreover, following preparation of monoclonal antibodies to DDR1, it was reported that these monoclonal antibodies bind to an epitope in the DS domain of DDR1, particularly to an epitope which has a tryptophan residue at position 53 at its center, and inhibit collagen-induced phosphorylation of DDR1. Although a remarkable antitumor activity was not demonstrated when said antibodies were used alone in a colorectal cancer xenograft model, antitumor activity was demonstrated when used together with irinotecan, a chemotherapeutic agent (Patent Document 3). However, an example of an anti-DDR1 antibody capable of demonstrating potent antitumor effects in vivo even when used alone remains to be found.